MITOL dysfunction causes dwarfism with anterior pituitary hypoplasia
- 1 September 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in The Journal of Biochemistry
- Vol. 168 (3), 305-312
- https://doi.org/10.1093/jb/mvaa050
Abstract
In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.Funding Information
- MEXT/JSPS KAKENHI (16K08246, 17K08793, 18H04869, 17H04053)
- Strategic Research Foundation at Private Universities (S1411014)
- the Tokyo Biochemical Research Foundation
- AMED (JP17gm5010002, 18gm5010002s1402, 19gm5010002h0003)
This publication has 39 references indexed in Scilit:
- Rapid Transition of NESTIN-Expressing Dividing Cells from PROP1-Positive to PIT1-Positive Advances Prenatal Pituitary DevelopmentJournal of Neuroendocrinology, 2013
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell deathProceedings of the National Academy of Sciences of the United States of America, 2012
- Mitochondrial Ubiquitin Ligase MITOL Ubiquitinates Mutant SOD1 and Attenuates Mutant SOD1-induced Reactive Oxygen Species GenerationMolecular Biology of the Cell, 2009
- Genetic approaches identify adult pituitary stem cellsProceedings of the National Academy of Sciences of the United States of America, 2008
- A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamicsThe EMBO Journal, 2006
- Homeodomain-Mediated β-Catenin-Dependent Switching Events Dictate Cell-Lineage DeterminationCell, 2006
- Domains of Pit-1 required for transcriptional synergy with GATA-2 on the TSHβ geneMolecular and Cellular Endocrinology, 2002
- Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation.Journal of Medical Genetics, 1996
- Transcriptional mechanisms in anterior pituitary cell differentiationCurrent Opinion in Genetics & Development, 1994